1-amino-3,3-bis(thienylalkyl)-1,3-dihydro-2H-indol-2-ones

ABSTRACT

This invention relates to 1,3-dihydro-1-(pyridinylamino)-2H-indol-2-ones of the formula ##STR1## where R 1 , R 2  and R 3  are independently hydrogen, loweralkyl, aryl, arylloweralkyl or heteroarylloweralkyl selected from the group consisting of pyridinylmethyl, pyridinylethyl, thienyhmethyl, thienylethyl; or R 2  and R 3  together form a cycloalkane ring of 4 to 6 carbons or a spiro-fused aryl cycloalkane or heterocycloalkyl selected from the group consisting of piperidine and tetrahydropyran; X and Y are independently hydrogen, halogen, hydroxy, loweralkyl, loweralkoxy, nitro, amino or trifluoromethyl; m and n are independently integers of 1 to 3, the pharmaceutically acceptable acid addition salts thereof and, where applicable the optical, geometrical and stereoisomers and racemic mixtures thereof. The compounds of this invention display utility as analgesics, anticonvulsants, for enhancing memory and for the treatment of Alzheimer&#39;s disease.

This is a division of prior application Ser. No. 08/243,654 filed May13, 1994, now U.S. Pat. No. 5,464,846, issued Nov. 7, 1995, which is acontinuation of application Ser. No. 07/961,947 filed Oct. 16, 1992,which is a division of application Ser. No. 07/736,366 filed Jul. 26,1991, now U.S. Pat. No. 5,179,119 which is a division of applicationSer. No. 07/535,640 filed Jun. 11, 1990, now U.S. Pat. No. 5,053,511which is a continuation-in-part of application Ser. No. 07/388,437 filedAug. 2, 1989 now U.S. Pat. No. 5,006,537.

This invention relates to compounds of the formula ##STR2## where R₁, R₂and R₃ are independently hydrogen, loweralkyl, aryl, arylloweralkyl orheteroarylloweralkyl selected from the group consisting ofpyridinylmethyl, pyridinylethyl, thienylmethyl, thienylethyl; or R₂ andR₃ together form a cycloalkane ring of 4 to 6 carbons or a spiro-fusedaryl cycloalkane or heterocycloalkyl selected from the group consistingof piperidine and tetrahydropyran; X and Y are independently hydrogen,halogen, hydroxy, loweralkyl, loweralkoxy, nitro, amino ortrifluoromethyl; m and n are independently integers of 1 to 3, thepharmaceutically acceptable acid addition salts thereof and, whereapplicable the optical, geometrical and stereoisomers and racemicmixtures thereof. The compounds of this invention display utility asanalgesics, anticonvulsants, for enhancing memory and for the treatmentof Alzheimer's disease.

Preferred embodiments of the invention are those of Compound I where R1is selected from hydrogen and loweralkyl; R₂ is selected from hydrogenand loweralkyl; R₃ is selected from hydrogen and loweralkyl.

Most preferred embodiments of the invention are those of Compound Iwhere R₁ is selected from loweralkyl; R₂ is selected from hydrogen; andR₃ is selected from hydrogen.

This invention also relates to compounds of the formula ##STR3## whereR₂, R₃, Y and n are as previously defined, which are useful asintermediates for the preparation of the target compounds of thisinvention.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all optical, geometrical andstereoisomers thereof and racemic mixtures where such isomers andmixtures exist, its well Its pharmaceutically acceptable acid additionsalts thereof and solvates thereof such as hydrates.

In the above definition, the term "lower" means the group it isdescribing contains from 1 to 6 carbon atoms. The term "alkyl" refers toa straight or branched chain hydrocarbon containing no unsaturation,e.g., methyl, ethyl, isopropyl, t-butyl, neopentyl, n-hexyl, etc.; theterm "arylloweralkyl" refers to a monovalent substituent which consistsof an "aryl" group e.g., phenyl, o-tolyl, m-methoxyphenyl, etc., asdefined by the formula ##STR4## where Z is as defined below, and m is aninteger of 1 to 3, linked through a loweralkylene group having its freevalance bond from a carbon of the loweralkylene group, and having aformula of ##STR5## where Z is hydrogen, halogen, loweralkyl,loweralkoxy, CF₃, NO₂ and NH₂, OH and m is as previously defined; theterm "alkylene" refers to a bivalent radical of the lower branched orunbranched alkyl group it is derived from having valence bonds from twoterminal carbons thereof; e.g., ethylene (--CH₂ CH₂ --), propylene(--CH₂ CH₂ CH₂ --), ##STR6## etc,; the term "heteroaryl" refers to aaromatic heterocyclic mono- or bicyclic radical, e.g., pyridinyl,thiophene, etc.; and the term "heteroarylloweralkyl" refers to aloweralkyl group having a heteroaryl substituent thereon; the term"alkoxy" refers to a monovalent substituent which consists of an alkylgroup linked through an ether oxygen having its free valence bond fromthe ether oxygen, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.;and the term "halogen" refers to a member of the halogen familyconsisting of fluorine, chlorine, bromine and iodine.

The compounds of the present invention are prepared in the followingmanner. The substituents are as defined above unless indicatedotherwise.

A 1-aminooxindole having the formula ##STR7## where R₁ is hydrogen orloweralkyl, in solution with a loweralkanol or phenolic solvent, i.e.,phenol, isopropanol, butanol, etc., is reacted with an optionallysubstituted halopyridine hydrochloride of the formula ##STR8## where Halis halogen and p is 1 or 2, to afford Compound I of the invention of theformula ##STR9##

The 1-aminooxindole, Compound III, is typically synthesized utilizingprocedures described in Baumgarten et al., J. Am. Chem, Soc. 82, 3977-82(1960), which discloses the formation of 1-aminooxindole by thereduction of 3-cinnolinol with zinc and H₂ SO₄ and by thermalcyclization of o-hydrazinophenylacetic acid.

Typically, the formation of Compound I is conducted under an inertatmosphere, i.e., nitrogen or argon, at a temperature of 80° C. to 150°C. for 1/2 to 24 hours.

To prepare Compound I where R₁ =alkyl, 1-aminooxindole is reacted with alower alkyl aldehyde, such as propionaldehyde, in the presence of acatalyst, i.e., p-toluenesulfonic acid to afford Compound V of theformula ##STR10## Compound V is in turn reduced with sodiumcyanoborohydride (NaBH₃ CN) to afford Compound VI of the formula##STR11## This reaction typically takes place in an lower alkanolsolvent, i.e., methanol, at a temperature of 0° to 50° C. for 0.25 to 6hours. The reduction using NaBH₃ CN is described in Borch et al., J. Am.Chem. Soc., 93, 2897, 1971.

Compound VI is reacted with a halopyridine hydrochloride i.e.,4-bromopyridine HCl or 4-chloropyridine HCl to give Compound I, where R₁=alkyl.

Compounds of the present invention are useful as analgesic agents due totheir ability to alleviate pain in mammals. The activity of thecompounds is demonstrated in the phenyl-para-quinone writhing assay inmice, a standard assay for analgesia [Proc. Soc. Exptl. Biol. Med., 95,729 (1957)]. Presented in Table 1 is the analgesic effect of some of thecompounds of the invention expressed as either the subcutaneous dose atwhich 50% of the phenyl-para-quinone induced writhing is inhibited inthe animals, i.e., the ED50 value, or as the % decrease in writhing at agiven dose.

                  TABLE 1                                                         ______________________________________                                                            ED.sub.50 or % Inhibition                                 Compound            of Writhing                                               ______________________________________                                        1,3-Dihydro-1-(4-pyridinyl-                                                                       ED.sub.50 = 0.69 mg/kg, s.c.                              amino)-2H-indol-2-one                                                         1,3-Dihydro-1-(propyl-4-pyridinyl-                                                                -58% at 20 mg/kg, s.c.                                    amino)-2H-indol-2-one                                                         Salicylic Acid (standard)                                                                         ED.sub.50 = 3.28 mg/kg, s.c.                              ______________________________________                                    

The analgesic relief of pain is achieved when the compounds of theinvention are administered to a subject requiring such treatment at aneffective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kgof body weight per day. A preferred effective dose within this range isfrom about 10 to 50 mg/kg of body weight per day. A particularlypreferred effective amount is about 30 mg/kg of body weight per day. Itis to be understood, however, that for any particular subject, specificdosage regimens should be adjusted according to the individual need andthe professional judgment of the person administering or supervising theadministration of the compound. It is further to be understood that thedosages set forth herein are examples only and that they do not, to anyextent, limit the scope or practice of the invention.

The compounds of the present invention are also useful in the treatmentof various memory dysfunctions characterized by decreased cholinergicfunction such as Alzheimer's Disease. This utility is demonstrated inthe Dark Avoidance Assay.

Dark Avoidance Assay

In this assay, mice are tested for their ability to remember anunpleasant stimulus for a period of 24 hours. A mouse is placed in achamber that contains a dark compartment; a strong incandescent lightdrives it to the dark compartment, where an electric shock isadministered through metal plates on the floor. The animal is removedfrom the testing apparatus and tested again, 24 hours later, for theability to remember the electric shock.

If scopolamine, an anticholinergic that is known to cause memoryimpairment, is administered before an animal's initial exposure to thetest chambers, the animal re-enters the dark compartment shortly afterbeing placed in the test chamber 24 hours later. The effect ofscopolamine is blocked by an active test compound, resulting in agreater interval before re-entry into the dark compartment.

The results for an active compound are expressed as the percent of agroup of animals in which the effect of scopolamine is blocked, asmanifested by an increased interval between being placed in the testchamber and re-entering the dark compartment. Presented in Table 2 isthe activity of some of the compounds of the invention in this assay.

                  TABLE 2                                                         ______________________________________                                                                  % of Animals With                                                   Dose      Scopolamine Induced                                                 (mg/kg of Memory Deficit                                      Compound        body wt)  Reversal                                            ______________________________________                                        1,3-Dihydro-1-(4-                                                                             0.31      27                                                  pyridinylamino)-2H-                                                                           0.63      27                                                  indol-2-one     1.25      27                                                  1,3-Dihydro-1-(propyl-4-                                                                      1.25      27                                                  pyridinylamino)-2H-indol-                                                     2-one                                                                         1,3-Dihydro-1-(3-fluoro-                                                                      1.0       27                                                  4-pyridinylamino)-2H-                                                                         3.0       27                                                  indol-2-one                                                                   1,3-Dihydro-3,3-dimethyl-                                                                     0.3       20                                                  1-(propyl-4-piperidinyl-                                                      amino)-2H-indol-2-one                                                         1,3-Dihydro-1-[(3-fluoro-                                                                     0.3       27                                                  4-pyridinyl)amino]-3-                                                                         3.0       20                                                  methyl-2H-indol-2-one                                                         hemifumarate                                                                  1,3-Dihydro-3,3-dimethyl-                                                                     0.3       21                                                  1-[4-(3-fluoropyridinyl)-                                                                     1.0       27                                                  propylamino]2H-indol-2-one                                                    1-Amino-3,3-bis(4-pyridi-                                                                     0.3       21                                                  nylmethyl)-1,3-dihydro-2H-                                                    indol-2-one                                                                   1-Amino-1,3-dihydrospiro-                                                                     0.3       21                                                  [2H-indene-2,3'-[3H]-                                                                         1.0       20                                                  indol]-2'(1'H)one                                                             1,3-Dihydro-1'-(propyl-4-                                                                     3.0       25                                                  pyridinylamino)spiro[2H-                                                      indene-2,3'-[3H]indol]-                                                       2'(1'H)-one                                                                   1'Methyl-1-(propyl-4-                                                                         1.0       20                                                  pyridinylamino)spiro-                                                         [3H-indole-3,4'-piperidin]-                                                   2(1H)-one                                                                     1,3-Dihydro-1-[(3-fluoro-                                                                     0.3       20                                                  4-pyridinyl)-propylamino]-                                                                    3.0       20                                                  2H-indol-2-one                                                                Tacrine (standard)                                                                            0.63      13                                                  Pilocarpine (standard)                                                                        1.25      19                                                  ______________________________________                                    

The compounds of the invention are also useful as anticonvulsants due totheir anticonvulsant activity in mammals. Anticonvulsant activity ismeasured in the male mouse using the supramaximal electroshock (SES)assay described in Arch. Int. Pharmacodyn. 92:97-107, 1952. In thisprocedure, groups of male mice (Charles River, CD-1, 18-30 gm) are used.Drugs are prepared using distilled water and, if insoluble, a surfactantis added. Control animals receive vehicle. Drugs are routinelyadministered interperitoneally (i.p.) The dosage volume is 10 ml/kg. Aprimary screen is given a 30 minute pretreat. The animals' eyes areplaced across the output terminals of an A.C. shocker that delivers 206volts rms for 300 msec. Electrode paste coats the animals' eyes at thepoint of contact with the terminals. A compound is considered to giveprotection if the mouse does not exhibit extensor tonus. Protection isexpressed as normalized percent inhibition relative to vehicle control.

The anticonvulsant activity of some of the compounds of this inventionis given below in Table 3.

                  TABLE 3                                                         ______________________________________                                        Compound             ED.sub.50 mg/kg i.p.                                     ______________________________________                                        1,3-Dihydro-1-(propyl-4-pyridinyl-                                                                 15.9                                                     amino)-2H-indol-2-one                                                         1,3-Dihydro-3,3-dimethyl-1-(propyl-                                                                30.7                                                     4-pyridinylamino)-2H-indol-2-one                                              Phenobarbital (standard)                                                                           8.4                                                      ______________________________________                                    

Effective quantities of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The compounds of the present invention, whileeffective themselves, may be formulated and administered in the form oftheir pharmaceutically acceptable addition salts for purposes ofstability, convenience or crystallization, increased solubility and thelike.

Preferred pharmaceutically acceptable addition salts include salts ofinorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric and perchloric acids; as well as organic acids such astartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of compound present in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel™, corn starch andthe like; a lubricant such as magnesium strearate or Sterotex®; aglidant such as colloidal silicon dioxide; and a sweetening agent suchas sucrose or saccharin or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring may be added. When the dosage unit formis a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as a fatty oil. Other dosage unit forms maycontain other various materials which modify the physical form of thedosage unit, for example, as coatings. Thus tablets or pills may becoated with sugar, shellac, or other enteric coating agents. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

Examples of the target compounds of this invention include:

1,3-Dihydro-1-[ethyl-(3-nitro-4-pyridinyl)amino]-3,3-dimethyl-2H-indol-2-one;

1,3-Dihydro- 1-[(3-fluoro-4-pyridinyl)propylamino]-2H-indol-2-one;

1,3-Dihydro-3-methyl-1-(4-pyridinylamino)-2H-indol-2-one;

1,3-Dihydro-3,3-dimethyl-1-(methyl-4-pyridinylamino)-2H-indol-2-one;

1,3-Dihydro-6-methyl-1-(4-pyridinylamino)-2H-indol-2-one;

1-[(3-Amino-4-pyridinyl)butylamino]-1,3-dihydro-3-methyl-2H-indol-2-one;

1,3-Dihydro-1-[(3-methyl-4-pyridinyl)propylamino]-3-phenylmethyl-2H-indol-2-one;

3,3-Diethyl- 1,3-dihydro- 1-[(3-ethyl-4-pyridinyl)amino]-2H-indol-2-one;

1,3-Dihydro-1-[(3-fluoro-4-pyridinyl)-1-(2-propenyl)amino]-2H-indol-2-one;

1,3-Dihydro-3-methyl-1-[(3-methyl-4-pyridinyl)-1-(2-propynyl)amino]-2H-indol-2-one;

1,3-Dihydro-1-[(3-phenylmethyl-4-pyridinyl)amino]-2H-indol-2-one;

1-[(3-Amino-4-pyridinyl)methylamino]-1,3-dihydro-3-propyl-2H-indol-2-one;

1,3-Dihydro-1-(propyl-3-pyridinylamino)-2H-indol-2-one;

1-[(4-Amino-3-pyridinyl)methylamino]-1,3-dihydro-3-propyl-2H-indol-2-one;

1-[(4-Fluoro-3-pyridinyl)propylamino]-1,3-dihydro-2H-indol-2-one;

1,3-Dihydro-1'-(4-pyridinylamino)spiro[2H-indene-2,3'-[3H]indol]-2'(1'H)-one.

Examples of the novel intermediate compounds of this invention include:

1-Amino-3,3-bis(4-pyridinylmethyl)- 1,3-dihydro-2H-indol-2-one;

1-Amino- 1,3-dihydro-5-methoxy-2H-indol-2-one.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees centigrade (°C.) unless otherwise designated.

EXAMPLE 1 1,3-Dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one

To a stirred solution of 1,3-dihydro-1-(propylamino)-2H-indol-2-one(10.4 g) and phenol (30.8 g), preheated to 150° C. under nitrogen, wasadded 4-bromopyridine hydrochloride (11.04 g) over 5 min. Heating wascontinued for 7 hours at which time the reaction mixture was cooled toroom temperature and made basic by slow addition of dilute aqueoussodium hydroxide. The product was extracted four times with ethylacetate and the combined organic layers back-extracted with diluteaqueous sodium hydroxide, washed with brine, and dried (K₂ CO₃).Filtration and concentration gave the crude product. Purification viaflash column chromatography (silica gel, EtOAc), preparative highperformance liquid chromatography (HPLC) (silica gel, EtOAc→2% Et₃N/0-7% MeOH/EtOAc), and a third column (alumina, EtOAc) followed.Recrystallization from ethyl acetate-pentane afforded 2.10 g (14%) of1,3-dihydro- 1 -(propyl-4-pyridinylamino)-2H-indol-2-one, as a solid,m.p. 140°-143° C.

Analysis: Calculated for C₁₆ H₁₇ N₃ O: 71.89%C 6.41%H 15.72%N Found:71.69%C 6.40%H 15.64%N

EXAMPLE 2 1,3-Dihydro-1-(4-pyridinylamino)-2H-indol-2-one

To a stirred solution of 1-amino-1,3-dihydro-2H-indol-2-one (10.0 g) andisopropanol (270 ml) was added 4-chloropyridine hydrochloride (15.21 g).The flask was fitted with a condensor and nitrogen inlet and flushedwith nitrogen. The reaction mixture was heated at reflux for 151/2hours. Upon cooling to room temperature, saturated aqueous sodiumbicarbonate was added to neutralize the hydrochloride salts. Solidsodium bicarbonate was added until gas evolution ceased. The resultingslurry was mixed with methanol-dichloromethane and filtered. The solidswere washed with methanol-dichloromethane and the combined filtrateconcentrated. Purification via flash column chromatography (silica gel,2% Et₃ N/0→10% MeOH/EtOAc) afforded fractions from which the productcrystallized. The mother liquor was concentrated and a second crop ofproduct was obtained. Obtained was 4.81 g (31%) of1,3-dihydro-1-(4-pyridinylamino)-2H-indol-2-one, as a solid, m.p.221°-224° C.

Analysis: Calculated for C₁₃ H₁₁ N₃ O: 69.32%C 4.92%H 18.65%N Found:69.20%C 4.91%H 18.64%N

EXAMPLE 3 1,3-Dihydro-1-(3-fluoro-4-pyridinylamino)-2H-indol-2-one

To a stirred solution of 1-amino-1,3-dihydro-2H-indol-2-one (10.03 g) inisopropanol (270 ml) was added 4-chloro-3-fluoropyridine hydrochloride(10.0 g). The flask was flushed with nitrogen and fitted with a refluxcondensor and nitrogen inlet. The reaction mixture was heated at refluxfor 22 hours. Upon cooling to room temperature, the reaction mixture waspoured into dilute aqueous sodium bicarbonate and ethyl acetate. Thelayers were separated and the aqueous layer extracted twice with ethylacetate and once with ether. The combined organic layers were washedwith brine and dried (K₂ CO₃). Filtration and concentration gave thecrude product.

Purification via preparative high pressure liquid chromatography (HPLC)(silica gel, 3% MeOH/DCM) followed by trituration with ether-pentaneafforded 4.4 g (30%) of1,3-dihydro-1-(3-fluoro-4-pyridinylamino)-2H-indol-2-one as a solid,m.p. 181°-183° C.

Analysis: Calculated for C₁₃ H₁₀ FN₃ O: 64.19%C 4.14%H 17.27%N Found:64.10%C 4.09%H 17.25%N

EXAMPLE 41,3-Dihydro-3,3-dimethyl-1-(propyl-4-pyridinylamino)-2H-indol-2-one

To a stirred solution of 1-amino-1,3-dihydro-3,3-dimethyl-2H-indol-2-one(7.35 g) and isopropanol (167 ml) was added 4-chloropyridinehydrochloride (8.15 g). The flask was flushed with nitrogen and fittedwith a condensor and nitrogen inlet. The reaction mixture was heated atreflux for 9 hours. Upon cooling to room temperature, the reactionmixture was poured into dilute aqueous sodium bicarbonate. The productwas extracted thrice with ethyl acetate and once with dichloromethane.The combined organic layers were washed with brine and dried (K₂ CO₃).Filtration and concentration gave the crude product. Purification viaflash column chromatography (silica gel, 2% Et₃ N/0-2% MeOH/ether)afforded 3.5 g (33%) of the desired product.

To a solution consisting of the above product (3.36 g) anddimethylformamide (120 ml), cooled to 0° C. under nitrogen, was addedsodium hydride (0.36 g, 97% dry). Stirring was continued at 0° C. for 35min at which time bromopropane (1.3 ml) was added dropwise. The reactionmixture was allowed to slowly warm over 11/2 hours, then poured intoethyl acetate and water. The layers were separated and the aqueous layerextracted with ethyl acetate. The combined organic layers wereback-washed with water, brine, and dried (K₂ CO₃). Filtration andconcentration gave the crude product. Purification via flash columnchromatography (silica gel, 2% Et₃ N/0-1% MeOH/ether) afforded 3.5 g(87%) of1,3-dihydro-3,3-dimethyl-1-(propyl-4-pyridinylamino)-2H-indol-2-one,m.p. 125°-127° C.

Analysis: Calculated for C₁₈ H₂₁ N₃ O: 73.19%C 7.17%H 14.23%N Found:73.33%C 7.20%H 14.20%N

EXAMPLE 51,3-Dihydro-1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-2H-indol-2-onehemifumarate

To a stirred solution of 1-amino-1,3-dihydro-3-methyl-2H-indol-2-one(8.40 g) and isopropanol (230 ml) was added 4-chloro-3-fluoropyridinehydrochloride (9.59 g). The flask was flushed with nitrogen, fitted witha reflux condensor and nitrogen inlet, and the mixture heated at refluxfor 7.5 hours. Additional 4-chloro-3-fluoropyridine hydrochloride (4.36g) was added and heating was continued for 6.25 hours. Upon cooling toroom temperature, the mixture was poured into dilute aqueous sodiumbicarbonate and dichloromethane-methanol. The layers were separated andthe aqueous layer was extracted with dichloromethane and the combinedorganic layers were washed with brine and dried (K₂ CO₃). Filtration andconcentration gave the crude product.

Purification via flash column chromatography (silica gel, 2%triethylamine/ether) afforded 5.40 g. The product was re-purified onanother column. The hemi-fumarate was prepared in absolute ethanol with1.0 eq of fumaric acid. Filtration afforded1,3-dihydro-1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-2H-indol-2-onehemifumarate, as a salt, m.p. 202+-202.5° C.

Analysis: Calculated for C₁₄ H₁₂ FN₃ O 0.5 C₄ H₄ O₄ : 60.94%C 4.48%H13.33%N Found: 60.73%C 4.36%H 13.21%N

EXAMPLE 61,3-Dihydro-1-(propyl-4-pyridinylamino)-3-spiro-1'-cyclopentan-2H-indol-2-one

To a stirred solution of1-amino-1,3-dihydro-1'-cyclopentan-2H-indol-2-one (9.6 g) andisopropanol (189 ml) was added 4-chloropyridine hydrochloride (8.1 g).The flask was flushed with nitrogen and fitted with a condenser andnitrogen inlet. The reaction mixture was heated at reflux for 17 hours.Upon cooling to room temperature, the reaction mixture was poured intodilute aqueous sodium bicarbonate. The product was extracted with ethylacetate (6×). The combined organic layers were washed with brine anddried (K₂ CO₃). Filtration and concentration gave the crude product.Purification via flash chromatography (silica gel, 2% triethylamine/0-2%methanol/ether) afforded 4.4 g of the desired product.

To a solution of the above product (4.4 g) and DMF (143 ml), cooled to0° C. under nitrogen, was added sodium hydride (0.42 g, 97% dry).Stirring was continued at 0° C. for 20 minutes at which timebromopropane (1.6 ml) was added dropwise. The reaction mixture wasallowed to slowly warm over 1 hour, then poured into ethyl acetate andwater. The layers were separated and the aqueous phase extracted withethyl acetate (3×). The combined organic layers were washed with brineand dried (K₂ CO₃). Filtration and concentration gave the crude product.

Purification via flash column chromatography (2% triethylamine/0-1%methanol/ether) afforded 4.6 g of the desired product. Recrystallizationfrom ether petroleum ether gave 1,3-dihydro-1-(propyl-4-pyridinylamino)-3-spiro-1'-cyclopentan-2H-indol-2-one, m.p.91°-93° C.

Analysis: Calculated for C₂₀ H₂₃ N₃ O: 74.74%C 7.21%H 13.07%N Found:74.92%C 7.39%H 13.13%N

EXAMPLE 71,3-Dihydro-3,3-dimethyl-1-[4-(3-fluoropyridinyl)-propylamino]2H-indol-2-on

To a stirred solution of 1-amino-1,3-dihydro-3,3-dimethyl-2H-indol-2-one(6.0 g) and isopropanol (136 ml) was added 4-chloro-3-fluoropyridinehydrochloride (4.41 g). The flask was flushed with nitrogen, fitted witha reflux condensor and nitrogen inlet, and the mixture heated at refluxfor 20 hours. Upon cooling to room temperature, the reaction mixture waspoured into dilute aqueous sodium bicarbonate and dichloromethane. Thelayers were separated and the organic layer washed with water (2×). Thecombined aqueous layers were back-extracted with dichloromethane and thecombined organic layers washed with brine and dried (K₂ CO₃).Filtration, concentration, and purification by flash columnchromatography (silica gel, 2% triethylamine/ether), and another column(silica gel, 0.50% ethyl acetate/hexane) afforded 2.12 g of the desiredintermediate.

To a solution consisting of the above product (2.12 g) and DMF (71 ml),cooled to 0° C. tinder nitrogen, was added sodium hydride (0.21 g, 97%dry). Stirring was continued at 0° C. for 35 minutes at which timebromopropane (0.78 ml) was added dropwise. The reaction mixture wasallowed to warm slowly over 1.5 hours, then poured into ethyl acetateand water. The layers were separated and the aqueous layer extractedwith ethyl acetate (3-4×). The combined organic layers werebacked-extracted with water (3×), brine, and dried (K₂ CO₃). Filtration,concentration, and purification via flash chromatography (silica gel,25-50% ethyl acetate/hexane) afforded 1.80 g of the desired product.Recrystallization from pentane gave1,3-dihydro-3,3-dimethyl-l-[4-(3-fluoropyridinyl)propylamino]2H-indol-2-one,m.p. 65°-67° C. Analysis: Calculated for C₁₈ H₂₀ FN₃ O: 68.99%C 6.43%H13.41%N Found: 68.99%C 6.36%H 13.44%N

EXAMPLE 8 1-Amino-1,3-dihydrospiro[2H-indene-2,3'-3H ]indol]-2'(1'H)one

To a slurry consisting of1,3-dihydro-1-[(phenylmethylene)amino]spiro[2H-indene-2,3'-[3H]indole]-2'(1'H)one(13.8 g), and absolute ethanol (300 ml) was added hydrazine hydrate(13.9 ml). The resulting mixture was heated at reflux for 3 hours,cooled to room temperature and the resulting precipitate removed byfiltration. The mother liquor was concentrated and the resulting oilsolidified upon addition of ethyl acetate-hexane. The resulting solidwas recovered by filtration. Additional product was obtained from themother liquor as above. Recrystallization from ethyl acetate afforded1-amino- 1,3-dihydrospiro[2H-indene-2,3'-[3H]indol]-2'(1'H)one, m.p.195°-197° C.

Analysis: Calculated for C₁₆ H₁₄ N₂ O: 76.78%C 5.64%H 11.19%N Found:76.33%C 5.54%H 11.06%N

EXAMPLE 9 1-Amino-3,3-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indol-2-one

To a solution consisting of3,3-bis-(4-pyridinylmethyl)-1,3-dihydro-1-[(phenylmethylene)amino]-2H-indol-2-one(7.84 g) and absolute ethanol (68 ml) was added hydrazine hydrate (6.4ml). The resulting mixture was heated at reflux for 5.75 hours, followedby cooling to 0° C. The product crystallized upon cooling. Filtrationand washing with ether-pentane afforded 2.50 g of1-amino-3,3-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indol-2-one.

Analysis: Calculated for C₂₀ H₁₈ N₄ O: 72.71%C 5.49%H 16.69%N Found:72.17%C 5.41%H 16.77%N

EXAMPLE 103,3-Bis(4-pyridinylmethyl)-1,3-dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one

To a stirred solution of1-amino-3,3-bis(4-pyridinylmethyl)-1,3-dihydro-2H-indol-2-one (2.85 g)and phenol (5.74 g), preheated to 155° C. with stirring was added4-chloropyridine hydrochloride (1.30 g) and p-toluenesulfonic acidH₂ O(150 mg). After 5 minutes of heating, additional 4-chloropyridinehydrochloride (2.60 g) was added. Heating was continued at 155° C. for13/4 hours. The mixture was cooled to room temperature, dissolved indilute aqueous sodium bicarbonate and dichloromethane, and the layersseparated. The layers were separated and the organic layer washed withdilute aqueous sodium bicarbonate. The combined aqueous layers wereback-extracted with dichloromethane and the combined organic layerswashed with brine and dried (K₂ CO₃). Filtration, concentration, andpurification (silica gel, 2% triethylamine/0-30% methanol/ether) gave2.20 g of the desired intermediate.

To a solution consisting of the above product (2.89 g) and DMF (50 ml),cooled to 0° C. under nitrogen, was added sodium hydride (0.19 g, 97%dry). Stirring was continued at 0° C. for 20 minutes at which timebromopropane (0.68 ml) was added dropwise. The reaction mixture wasallowed to warm to room temperature, poured into water, and the productextracted with ether and dried (K₂ CO₃). Filtration and concentrationgave the product which was recrystallized from ethyl acetate affording1.85 g of3,3-bis(4-pyridinylmethyl)-1,3-dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one,m.p. 182°-184° C.

Analysis: Calculated for C₂₈ H₂₇ N₅ O: 74.81%C 6.05%H 15.58%N Found:74.98%C 6.12%H 15.57%N

EXAMPLE 111.3-Dihydro-1'-(propyl-4-pyridinylamino)spiro-2H-indene-2,3'-[3H]indo]-2'(1'H)-one

To a stirred solution ofI-amino-1,3-dihydrospiro[2H-indene-2,3'[3H]indol]-2'(1'H)-one (2.84 g)and isopropanol (45 ml) was added 4-chloropyridine hydrochloride (1.88g). The flask was flushed with nitrogen, fitted with a reflux condenserand nitrogen inlet, and the mixture heated at reflux for 17 hours. Uponcooling to room temperature, the reaction mixture was poured into diluteaqueous sodium bicarbonate and dichloromethane. The layers wereseparated and the organic layer washed with water (2×). The combinedaqueous layers were back-extracted with dichloromethane and the combinedorganic layers washed with brine and dried. (K₂ CO₃). Filtration andconcentration afforded the crude intermediate.

A flask containing the intermediate (11.4 mmol) was flushed withnitrogen and DMF (114 ml) was added. Upon cooling to 0° C. undernitrogen, sodium hydride (0.37 g, 97% dry) was added with stirring.After 10 minutes, bromopropane (1.36 ml) was added dropwise. Thereaction mixture was allowed to warm slowly to room temperature, thenpoured into water and ethyl acetate. The layers were separated and theaqueous layer extracted with ethyl acetate (3×). The combined organiclayers were washed with water, brine, and dried (K₂ CO₃). Filtration,concentration, and purification via flash column chromatography (silicagel, 2% triethylamine/ether) afforded 2.50 g of1,3-dihydro-1'-(propyl-4-pyridinylamino)spiro[2H-indene-2,3'-[3H]indol]-2'(1'H)-one,m.p. 159°∝161° C.

Analysis: Calculated for C₂₄ H₂₃ N₃ O: 78.02%C 6.27%H 11.37%N Found:78.02%C 6.33%H 11.35%N

EXAMPLE 121'Methyl-1-(propyl-4-pyridinylamino)spiro-[3H-indole-3,4'-piperidin]-2(1H)-one

To a stirred solution consisting of 1-amino-1'-methylspiro[3H-indole-34'-piperidin]-2(1H)-one (3.77 g), phenol (11.1 g), and p-toluenesulfonicacid hydrate (0.10 g), heated at 150° C, was added 4-chloropyridinehydrochloride (2.45 g). Additional 4-chloropyridine hydrochloride (2.45g) was added after 25 minutes and again (0.73 g) after an additional 75minutes. The reaction mixture was stirred an additional 40 minutes,cooled to room temperature, and poured into dichloromethane and diluteaqueous sodium bicarbonate. The layers were separated and the aqueouslayer extracted twice with dichloromethane and once with ether. Thecombined organic layers were washed with water and brine, and dried (K₂CO₃). Filtration and concentration afforded the crude product.Purification via flash column chromatography (silica gel, 2%triethylamine/0-20% methanol/ethyl acetate) afforded 4.40 g of thedesired intermediate.

To a solution consisting of the above intermediate (4.40 g) and DMF (130ml) cooled to 0° C. under nitrogen was added sodium hydride (0.39 g, 97%dry). Stirring was continued at 0° C. for 25 minutes at which timebromopropane (1.42 ml) was added dropwise. The reaction mixture wasallowed to warm to room temperature, stirred an additional 2 hours, thenpoured into water and ethyl acetate. The layers were separated and theaqueous layer extracted with ethyl acetate (3×) and ether (1×). Thecombined organic layers were washed with water (2×), brine, and dried(K₂ CO₃). Filtration, concentration, and purification via flash columnchromatography (silica gel, 2% triethylamine/0-20% methanol/ethylacetate) afforded 4.17 g of the desired product. Decolorization withactivated carbon in ethyl acetate gave1'methyl-1-(propyl-4-pyridinylamino)spiro[3H-indole-3,4'-piperidin]-2(1H)-one,as a solid, m.p. 125°-127° C.

Analysis: Calculated for C₂₁ H₂₆ N₄ O: 71.97%C 7.48%H 15.99%N Found:71.64%C 7.41%H 15.85%N

EXAMPLE 131,3-Dihydro-1-[(3-fluoro-4-pyridinyl)propylamino]-2H-indol-2-one

To a stirred solution consisting of1,3-dihydro-1-propylamino-2H-indol-2-one (5.06 g), phenol (13.2 g) andp-toluenesulfonic acid hydrate (0.25 g), heated at 150° C., was added4-chloro-3-fluoropyridine hydrochloride (5.37 g). Heating was continuedat 150° C. for 10.75 hours at which time additional4-chloro-3-fluoropyridine (2.05 g) was added and heating continued anadditional 6.5 hours. Upon cooling to room temperature, the reactionmixture was dissolved in dichloromethane and dilute aqueous sodiumbicarbonate. The layers were separated and the organic layer extractedwith dilute aqueous sodium bicarbonate (2×). The combined aqueous layerswere back-extracted with dichloromethane and ether. The combined organiclayers were washed with brine, dried (K₂ CO₃), filtered, andconcentrated. Purification via flash column chromatography (silica gel,2% triethylamine/ether) and another column (silica gel, EtOAc) affordedthe desired product as a solid.

The reaction was repeated with the amine (6.09 g) and4-chloro-3-fluoropyridine hydrochloride (6.00 g) in phenol (13.6 g) andheated for 17.5 hours. The reaction mixture was treated as above andcombined with the above product. Recrystallization from ether/pentaneafforded 1.20 g of1,3-dihydro-1-[(3-fluoro-4-pyridinyl)propylamino]-2H-indol-2-one, as asolid, m.p. 113.5°-115.5° C.

Analysis: Calculated for C₁₆ H₁₆ FN₃ O: 67.35%C 5.65%H 14.73%N Found: :67.20%C 5.67%H 14.71%N

EXAMPLE 14 1,3-Dihydro-5-methoxy-1-(4-pyridinylamino)-2H-indol-2-one

A solution consisting of 1-amino-1,3-dihydro-5-methoxy-2H-indol-2-one(5.00 g), 4-chloropyridine hydrochloride (4.00 g), and1-methyl-2-pyrrolidinone (40 ml) was heated in a 105° C. oil bath for 2hours after which time more 4-chloropyridine hydrochloride (0.21 g) wasadded and heating was continued an additional 1 hour. Upon cooling toroom temperature, dilute aqueous sodium bicarbonate and ethyl acetatewere added. The layers were separated and the aqueous layer extractedwith ethyl acetate (3×). The combined organic layers were washed withwater, brine, and dried (K₂ CO₃). Filtration and concentration gave thecrude product.

Purification via flash column :chromatography (silica gel, 2%triethylamine/0-20% methanol/ethyl acetate) and another column (silicagel, 2% triethylamine/0-5% methanol/ethyl acetate) afforded 2.4 g of thedesired product as an oil. Dissolution in ethyl acetate followed byaddition of ether gave1,3-dihydro-5-methoxy-1-(4-pyridinylamino)-2H-indol-2-one, as a solid,m.p. 169°-171° C.

Analysis: Calculated for C₁₄ H₁₃ N₃ O₂ : 65.87%C 5.13%H 16.46%N Found:65.62%C 5.15%H 16.15%N

EXAMPLE 15 1-Amino-1,3-dihydro-5-methoxy-2H-indol-2-one

5-Methoxy-2-nitrophenyl acetic acid (40 g) was reduced in a ParrHydrogenation Apparatus as an aqueous sodium hydroxide solution (15.2 gof 50% aq. NaOH diluted to 170 ml with distilled water) with 10% Pd-C(2.00 g) at a pressure of 65 psig hydrogen. Upon no further uptake ofhydrogen, the catalyst was removed by filtration through a pad ofcelite. The resulting solution was treated with sodium nitrite (13.37 g)and cooled in a 0° C. water bath. This solution was added slowly toconc. hydrochloric acid (144 ml) with stirring at a rate so as tomaintain an internal temperature of <+15° C. The resulting mixture wasstirred an additional 20 minutes while cooling to 0°-5° C.

To a solution consisting of stannous chloride monohydrate (129.5 g) andconc. hydrochloric acid (130 ml) stirred in a 0° C. ice bath was addedthe above mixture over about 10 minutes. Stirring was continued for45-60 minutes after addition, after which time, the resultingprecipitate was recovered by filtration. The precipitate was air dried,then slurried in water (345 ml) and heated to reflux. Upon cooling toroom temperature, the reaction mixture was basified (pH 12) by additionof aqueous sodium hydroxide. The product was extracted withdichloromethane (3×) and the combined organic layers washed with brineand dried (K₂ CO₃). Filtration and partial concentration gave theanalytical sample. Further concentration afforded 15.0 g of1-amino-1,3-dihydro-5-methoxy-2H-indol-2-one, as a solid, m.p.136°-138°.

Analysis: Calculated for C₉ H₁₀ N₂ O₂ : 60.67%C 5.66%H 15.72%N Found:60.66%C 5.65%H 15.64%N

We claim:
 1. A compound of the formula ##STR12## wherein R₂ and R₃ areindependently thienylmethyl or thienylethyl; Y is hydrogen, halogen,hydroxy, loweralkyl, loweralkoxy, nitro, amino, or trifluoromethyl; n is1, 2, or 3; the geometric isomer thereof, the optical isomer thereof,the racemic mixture thereof, or the pharmaceutically acceptable acidaddition salt thereof.
 2. A pharmaceutical composition for enhancingmemory which comprises an effective memory enhancing amount of acompound as defined in claim 1 and a pharmaceutically acceptable carrierthereof.
 3. A method of treating a mammal in need of memory enhancementwhich comprises administering to a mammal a memory enhancing effectiveamount of a compound as defined in claim 1.